Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer

Neoadjuvant Androgen Deprivation and Enzalutamide: Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer

Background:

• There are several ways to treat prostate cancer. Researchers want to see how well a certain kind of imaging helps detect prostate cancer. They also want to see if a particular drug combination used before surgery will benefit people with prostate cancer that hasn't spread in the body (non-metastatic). The combination will be androgen deprivation therapy and enzalutamide.
• The combination of androgen deprivation therapy and enzalutamide has been shown to make patients with advanced (metastatic disease) live longer. The investigators want to see if using it earlier can increase cure rate of surgery and identify genetic or molecular characteristics that are associated with better outcomes.

Objectives:

- To develop better ways of detecting prostate cancer before and after pre-operative treatment.

Eligibility:

- Men at least 18 years old with non-metastatic prostate cancer. They must be candidates for a radical prostatectomy.

Design:

• Participants will be screened with medical history, physical exam, and blood tests. They will have scans and X-rays.
• Before starting the study drugs, participants will have:
• Vital signs taken, medical history, and blood tests.
• Electrocardiogram (ECG) heart test, with patches stuck on the skin.
• Small piece of tumor removed (biopsy) using image guidance from magnetic resonance imaging (MRI) and ultrasound.
• 3T multi-parametric magnetic resonance imaging (mpMRI). Participants will lie on a table that slides into a metal cylinder. A probe will be inserted in the rectum. They will be in the scanner for about 60 minutes, lying still. The scanner makes loud knocking sounds. Participants will get earplugs.
• Participants will take the 2 study drugs for 6 months.
• Enzalutamide is taken as 4 pills once a day.
• Androgen deprivation therapy is given by injection 2 times over 6 months.
• During these 6 months, participants will visit the clinic monthly. They will have physical exam, vital signs, and blood drawn.
• After finishing the study drugs, participants will have another 3T mpMRI. Then they will have prostate removal surgery.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Goserelin; Drug: Enzalutamide; Device: mpMRI

Detailed Description

Background:

• Most men diagnosed with prostate cancer will present with intermediate or high-risk disease
• Many develop castrate resistant prostate cancer (CRPC) as curative strategies are often unsuccessful
• Treatment options typically involve radical prostatectomy (RP) or radiation therapy (RT) in combination with androgen deprivation therapy (ADT)
• Even when cancers are initially sensitive to ADT, resistance ultimately emerges either through clonal selection or through a variety of adaptive mechanisms (secondary resistance).
• The recent introduction of novel androgen pathway inhibitors offers an opportunity to potentially improve the cure rate of men with intermediate and high risk localized prostate cancer
• There remains a great need for improved techniques to determine mechanisms of treatment response and resistance.

Objectives:

-To test the feasibility of multi parametric magnetic resonance imaging (mpMRI) for the localization and detection of focal prostate cancer both before and after pre-operative treatment with ADT and enzalutamide.

Eligibility:

• Patients with nonmetastatic castration sensitive prostate cancer with intermediate or high-risk features
• Patients with testosterone levels greater than or equal to 100 ng/dL.
• Eastern Cooperative Oncology Group (ECOG) 0-1.

Design:

• Patients will be treated with ADT and enzalutamide for 6 months
• Two 3T mpMRI endorectal examinations (One at screening and after 6 month of treatment)
• Screening biopsy (magnetic resonance (MR)/ultrasound (US) guided) samples
• Standard of care prostatectomy (RP) following post treatment mpMRI
• All tumor specimens will undergo genomic analysis

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Patients must have histologically or cytologically confirmed prostate cancer confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) or Pathology Department at Walter Reed Bethesda

• Must have previously untreated (with definitive therapy) prostate cancer with intermediate or high risk features defined as:

  • Intermediate risk:

    • Prostate-specific antigen, (PSA) level is between 10 and 20 ng/ml or
    • Gleason score is 7 or
    • Stage T2b or T2c

  • High Risk:

    • Gleason 8 and higher OR
    • PSA greater than 20 at the time of diagnosis OR
    • Seminal vesicle involvement OR
    • Possible (on magnetic resonance imaging (MRI) Extra-capsular extension (T3 disease)
• Patients must be eligible for and must be planning to undergo radical prostatectomy
• Patients must have testosterone levels greater than or equal to 100 ng/dL

• Men age greater than or equal to 18 years.

  • Children are excluded because prostate cancer is not common in pediatric populations.
  • Women are not eligible because this disease occurs only in men.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
• Patients must have normal organ and marrow function as defined below:
• Hemoglobin greater than or equal to 9 g/dL
• leukocytes greater than or equal to 3,000/mcL
• absolute neutrophil count greater than or equal to 1,500/mcL
• platelets greater than or equal to 150,000/mcL
• total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase(SGOT)/Alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT) less than or equal to 3 X institutional upper limit of normal
• creatinine within normal institutional limits

OR

• creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
• The effects of enzalutamide on the developing human fetus are unknown. For this reason and because androgen receptor antagonists as well as other therapeutic agents used in this trial are known to be teratogenic, male participants and their female partners of child bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence). Male participants should use a condom if having intercourse with a pregnant woman. Additionally, a condom plus another effective method of birth control is recommended during therapy and for 3 months after treatment for male participants having intercourse with a woman of reproductive potential. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.
• Ability of subject to understand and the willingness to sign a written informed consent document.
• Willingness to undergo biopsy.
• Ability to detect lesions within prostate on magnetic resonance imaging (MRI) for biopsy
• Willingness to travel to National Institutes of Health (NIH) for follow-up visits.

EXCLUSION CRITERIA:

• Patients who are receiving any other investigational agents (in the past 28 days) or herbal medications (within 1 day).
• Patients with distant metastatic disease beyond N1(regional) lymph nodes on conventional imaging studies (Computed tomography (CT), MRI or Bone Scan).
• Patients who have received any prior therapy for prostate cancer with surgery, radiation, and/or chemotherapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or other agents used in study.
• Clinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months as confirmed by an electrocardiogram (ECG).

• Contraindication to biopsy:

  • Bleeding disorders
  • Prothrombin Time (PT)/Partial Thromboplastin Time (PTT) greater than or equal to 1.5 times the upper limit of normal
  • Artificial heart valve

• Contraindication to MRI:

  • Patients weighing more than weight limit for the scanner tables
  • Allergy to MR contrast agent
  • Patients with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable electronic device
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with known human immunodeficiency virus (HIV) are eligible. These patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. In addition, if patients are receiving combination antiretroviral therapy, there is potential for pharmacokinetic interactions with enzalutamide. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
• Patients with known active treatment for Hepatitis B and C infections.
• Patients who are taking medications that are strong inhibitors of Cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (PgP) and need to remain on these medications. For a current table of Substrates, Inhibitors and Inducers please access the following website:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm

• History of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack, or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization).
• Other medications used for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter prostate specific antigen (PSA) (eg phytoestrogens and saw palmetto) cannot be taken while patients are receiving enzalutamide
• Patients with a malignancy within the past 3 years for which study drugs or a prostatectomy is a contraindication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/Arm 1- Enzalutamide and Goserelin; Patients will have an multi-parametric magnetic resonance imaging (mpMRI) guided biopsy, then receive enzalutamide and goserelin subcutaneous (SC) treatment for 6 months followed by a second mpMRI examination.	Drug: Goserelin; 10.8mg administered subcutaneously every 12 weeks (2 doses); Other Names: Zoladex; Drug: Enzalutamide; 160mg orally, daily for 24 weeks; Other Names: ASP-9785; Device: mpMRI; Multiparametric MRI - One at baseline and after 6 months of treatment; Other Names: multi-parametric magnetic resonance imaging

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Tumor Volume Burden at Baseline Multi-parametric Magnetic Resonance Imaging (mpMRI) Before and After Surgery	The prostate lesion is contoured manually by an expert radiologist. Research software (mim-vista) calculates the volume. Greater tumor volumes may indicate higher prostate tumor growth.	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Nuclear Androgen Receptor (AR) Level in Biopsy Specimens Versus Residual Tumors	The effect of intense androgen suppression and inhibition was measured on tumors using anti-AR immunostains of biopsy and surgical specimens. Detection of tumor nuclear AR was quantified on a per-nucleus basis using computer-aided image analysis with Definiens Developer XD 64, grouping nuclei into high, medium, low, and absent bins, a histology score was assigned to each sample. Nucleus classification is low vs. med. at 0.7; med. vs. high at 0.95. Definiens reported the total # of positively stained nuclei or cells, along with the distribution of low-, med.-, and high-intensity stained nuclei/cells for ea. tumor focus. A %positive index score was calculated using a weighted avg. divided by the total # of objects, where index = [ (1 × nuclei/cells stained low) + (2 × nuclei/cells stained med.) + (3 × nuclei/cells stained high) ](3 × total nuclei).	6 months
Median Prostate Lesion Volume Before and After Treatment	Prostate lesion volumes on baseline and post-treatment multiparametric magnetic resonance imaging (mpMRI) were calculated from T2W-MRI sequences using software embedded in the PACS after manual contouring by the same radiologist. Lesion volume scores were categorized as low (2 or fewer positive sequences), moderate (3 positive sequences) and high (4 positive sequences). Lesion volume values are in cubic centimeters (cc's).	Baseline and 6 months
Number of Participants With a Complete Response	Complete response was evaluated after neoadjuvant treatment with androgen deprivation therapy (ADT) and enzalutamide and assessed by pathologic exam. Pathologic complete response: the absence of residual invasive cancer confirmed by immunohistochemistry (IHC).	After neoadjuvant treatment with androgen deprivation therapy (ADT) and enzalutamide, approximately 6 months
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Date treatment consent signed to date off study, approximately 51 months and 2 days.
Number of Prostate Lesions Detected Within the Study Population at Baseline Multi-parametric Magnetic Resonance Imaging (mpMRI) and 6 Months After Enzalutamide Plus Androgen Deprivation Therapy (ADT)	Prostate lesion volumes on baseline and post-treatment mpMRI were calculated from T2W-MRI sequences using software embedded in the PACS after manual contouring by the same radiologist.	Baseline and 6 months
Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Sensitivity	The Youden index was used as a measure for evaluating biomarker effectiveness and was calculated to determine the cutoffs that gave the optimal combination of sensitivity and specificity for patient response to treatment. The index is: J=sensitivity + specificity -1. Its value ranges from 0 through 1 (inclusive). A value of 1 indicates that there are no false positives or false negatives, i.e. the test is perfect. The index gives equal weight to false positive and false negative values, so all tests with the same value of the index give the same proportion of total misclassified results. Sensitivity and specificity are the probability of truly identifying relative tumor burden on multiparametric magnetic resonance imaging (mpMRI) respectively at a statistically established cut point.	6 months
Number of Participants With Reduction in Phosphatase and Tensin Homolog (PTEN) Levels	PTEN level reduction was evaluated using immunohistochemistry in post treatment specimens. For anti-PTEN immunohistochemistry, a case was considered PTEN-reduced (abnormal) if at least 5% of tumor cells demonstrated reduced PTEN intensity relative to PTEN in benign cells (lower than 5%, then abnormal).	post treatment, approximately 1-3 months
Number of Participants With Positive Erythroblast Transformation-specific (ETS)-Related Gene (ERG) Protein Overexpression	ERG protein overexpression was evaluated using immunohistochemistry in post treatment specimens. A positive ETS-related ERG overexpression is a bad outcome.	Approximately one month-3 months post-treatment
Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Specificity	The Youden index was used as a measure for evaluating biomarker effectiveness and was calculated to determine the cutoffs that gave the optimal combination of sensitivity and specificity for patient response to treatment. The index is: J=sensitivity + specificity -1. Its value ranges from 0 through 1 (inclusive). A value of 1 indicates that there are no false positives or false negatives, i.e. the test is perfect. The index gives equal weight to false positive and false negative values, so all tests with the same value of the index give the same proportion of total misclassified results. Sensitivity and specificity are the probability of truly identifying relative tumor burden on multiparametric magnetic resonance imaging (mpMRI) respectively at a statistically established cut point.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Any Grade 1 Adverse Events in More Than One Patient and Grades 2 -3 Attributable to Research	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event (i.e., Grade 1) is any untoward medical occurrence. A serious adverse event (i.e., Grade 2-3) is an adverse event or suspected adverse reaction that results in an adverse drug experience, and/or disruption of the ability to conduct normal life functions attributable to the research.	Date treatment consent signed to date off study, approximately 51 months and 2 days.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Fatima Karzai, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Karzai F, Walker SM, Wilkinson S, Madan RA, Shih JH, Merino MJ, Harmon SA, VanderWeele DJ, Cordes LM, Carrabba NV, Bright JR, Terrigino NT, Chun G, Bilusic M, Couvillon A, Hankin A, Williams MN, Lis RT, Ye H, Choyke PL, Gulley JL, Sowalsky AG, Turkbey B, Pinto PA, Dahut WL. Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response. Clin Cancer Res. 2021 Jan 15;27(2):429-437. doi: 10.1158/1078-0432.CCR-20-2344. Epub 2020 Oct 6.
• Gold SA, VanderWeele DJ, Harmon S, Bloom JB, Karzai F, Hale GR, Marhamati S, Rayn KN, Mehralivand S, Merino MJ, Gulley JL, Bilusic M, Madan RA, Choyke PL, Turkbey B, Dahut W, Pinto PA. mpMRI preoperative staging in men treated with antiandrogen and androgen deprivation therapy before robotic prostatectomy. Urol Oncol. 2019 Jun;37(6):352.e25-352.e30. doi: 10.1016/j.urolonc.2019.01.012. Epub 2019 Apr 15.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2015
• Primary Completion (Actual): December 1, 2019
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: April 28, 2015
• First Submitted That Met QC Criteria: April 28, 2015
• First Posted (Estimated): April 30, 2015

Study Record Updates

• Last Update Posted (Actual): July 25, 2023
• Last Update Submitted That Met QC Criteria: June 30, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Prostatectomy; Multiparametric MRI; Non-Metastatic; Focal Prostate Cancer; Normal Testosterone
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Goserelin
• Other Study ID Numbers: 150124 (FDA (IND)); 15-C-0124

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No